Stem Cell–Related “Self-Renewal” Signature and High Epidermal Growth Factor Receptor Expression Associated With Resistance to Concomitant Chemoradiotherapy in Glioblastoma

作者：Anastasia Murat, Eugenia Migliavacca, Thierry Gorlia, Wanyu L. Lambiv, Tal Shay, Marie‐France Hamou, Nicolas de Tribolet, Luca Regli, Wolfgang Wick, Mathilde C.M. Kouwenhoven, Johannes A. Hainfellner, Frank L. Heppner, Pierre‐Yves Dietrich, Yitzhak Zimmer, J. Gregory Cairncross, Robert-Charles Janzer, Eytan Domany, Mauro Delorenzi, Roger Stupp, Monika E. Hegi · 发表于：Journal of Clinical Oncology · 年份：2008 · DOI：10.1200/jco.2007.15.7164 · 被引用次数：743 · 研究领域：Glioma Diagnosis and Treatment、Cancer Cells and Metastasis、Angiogenesis and VEGF in Cancer

PURPOSE: Glioblastomas are notorious for resistance to therapy, which has been attributed to DNA-repair proficiency, a multitude of deregulated molecular pathways, and, more recently, to the particular biologic behavior of tumor stem-like cells. Here, we aimed to identify molecular profiles specific for treatment resistance to the current standard of care of concomitant chemoradiotherapy with the alkylating agent temozolomide. PATIENTS AND METHODS: Gene expression profiles of 80 glioblastomas were interrogated for associations with resistance to therapy. Patients were treated within clinical trials testing the addition of concomitant and adjuvant temozolomide to radiotherapy. RESULTS: An expression signature dominated by HOX genes, which comprises Prominin-1 (CD133), emerged as a predictor for poor survival in patients treated with concomitant chemoradiotherapy (n = 42; hazard ratio = 2.69; 95% CI, 1.38 to 5.26; P = .004). This association could be validated in an independent data set. Provocatively, the HOX cluster was reminiscent of a "self-renewal" signature (P = .008; Gene Set Enrichment Analysis) recently characterized in a mouse leukemia model. The HOX signature and EGFR expression were independent prognostic factors in multivariate analysis, adjusted for the O-6-methylguanine-DNA methyltransferase (MGMT) methylation status, a known predictive factor for benefit from temozolomide, and age. Better outcome was associated with gene clusters characterizing features of tumor...